tbuckley/cabot-search huggingface dataset:
Letter to the editor: Disrupted BRCA1‐PALB2 interaction induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through cGAS‐STING pathway
Authors: Jun Cao, Dou‐Sheng Bai
Journal: Hepatology (2022)

To the editor, We followed with interest in the report by Hui et al. that DNA damage caused by a defective breast cancer (BRCA) pathway induces tumor immunosuppression and T‐lymphocyte infiltration in HCC through the cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway, providing new insight into the interaction between tumor cells and the tumor microenvironment that may help improve anti‐PD1 (programmed death 1) therapy for HCC response.1 In recent years, anti‐PD1 therapy is facing great challenges in HCC because of the complex tumor immune microenvironment (TIME). We appreciate the investigators' work on the research of TIME remodeling and proposing new treatments for the future. However, after reading this article, we want to highlight some key issues in this study. First, it is known that, on one hand, activation of cGAS‐STING can repolarize tumor‐promoting M2‐type macrophages into M1‐type macrophages; on the other hand, it can induce interferon production to promote dendritic cell (DC) maturation, which mediates CD8+ T‐cell activation to provide tumor regression.2 The investigators elucidated activation of the cGAS‐STING signaling pathway in M1 macrophages and exhibited dramatic immune microenvironment remodeling. However, they did not mention the DCs that are important to HCC anti‐PD1 treatment. This may illustrate a new mechanism of DC maturation caused by DNA damage. Second, in this research, the investigators analyzed the colocalization of CD11c (M1 macrophage marker) in tumor tissues using multiplex immunofluorescence (IF). It is known that CD11c is a commonly used marker of DCs and macrophages. CD11c can be used as a marker of M1 macrophages only in human tissues. When CD11c is used in mouse tissues, it can only label DCs.3 Multiplex IF is not sufficient to prove that cGAS‐STING signaling is activated in the M1 macrophages of Palb2MUT HCC tumors. Therefore, flow cytometry combined with multiple IF will be more rigorous in the study of tumor immune remodeling. Finally, further clinical studies with more samples will serve to elucidate results in HCC.
Physiological Chemistry. A Text-Book and Manual for Students.
Journal: JAMA (1921)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Transcription Factor GATA4 Regulates Cell Type–Specific Splicing Through Direct Interaction With RNA in Human Induced Pluripotent Stem Cell–Derived Cardiac Progenitors
Authors: Lili Zhu, Krishna Choudhary, Barbara Gonzalez-Teran, Yen-Sin Ang, Reuben Thomas, Nicole R. Stone, Lei Liu, Ping Zhou, Chenchen Zhu, Hongmei Ruan, Yu Huang, Shibo Jin, Angelo Pelonero, Frances Koback, Arun Padmanabhan, Nandhini Sadagopan, Austin Hsu, Mauro W. Costa, Casey A. Gifford, Joke G. van Bemmel, Ruth Hüttenhain, Vasanth Vedantham, Bruce R. Conklin, Brian L. Black, Benoit G. Bruneau, Lars Steinmetz, Nevan J. Krogan, Katherine S. Pollard, Deepak Srivastava
Journal: Circulation (2022)

GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors.We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4's novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors.We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms.This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.
Blockade of T‐cell receptor with Ig and ITIM domains elicits potent antitumor immunity in naturally occurring HBV‐related HCC in mice
Authors: Yuwei Wu, Xiaolei Hao, Haiming Wei, Rui Sun, Yongyan Chen, Zhigang Tian
Journal: Hepatology (2022)

Background and Aims: Chronic HBV infection is the leading cause of HCC and a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV‐related HCC is currently unavailable. This study evaluated the therapeutic potential of T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade in HBV‐related HCC. Approach and Results: A mouse model of spontaneous HBV‐related HCC was generated by replacing wild‐type hepatocytes with HBsAg + hepatocytes (namely HBs‐HepR mice). The tumors in HBs‐HepR mice were inflammation‐associated HCC, similar to HBV‐related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine‐induced HCC, TGF‐β‐activated kinase 1 knockout–induced HCC, HCC in a stelic animal model, or NASH‐induced HCC. HCC in HBs‐HepR mice was characterized by an increased number of CD8 + T cells, whereas the production of IL‐2, TNF‐α, and interferon‐gamma (IFN‐γ) by intrahepatic CD8 + T cells was decreased. Increased expression of TIGIT on CD8 + T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs‐HepR mice. TIGIT blockade reinvigorated intrahepatic CD8 + T cells with increased TNF‐α and IFN‐γ production and an increased number of CD8 + T cells in tumors, thereby slowing the development of HCC in HBs‐HepR mice. Blocking PD‐L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the antitumor activity of CD8 + T cells during the progression of HBV‐related HCC in a spontaneous HCC mouse model.
Single-cell analyses reveal early thymic progenitors and pre-B cells in zebrafish
Authors: Sara A. Rubin, Chloé S. Baron, Cecilia Pessoa Rodrigues, Madeleine Duran, Alexandra F. Corbin, Song P. Yang, Cole Trapnell, Leonard I. Zon
Journal: The Journal of Experimental Medicine (2022)

The zebrafish has proven to be a valuable model organism for studying hematopoiesis, but relatively little is known about zebrafish immune cell development and functional diversity. Elucidating key aspects of zebrafish lymphocyte development and exploring the breadth of effector functions would provide valuable insight into the evolution of adaptive immunity. We performed single-cell RNA sequencing on ∼70,000 cells from the zebrafish marrow and thymus to establish a gene expression map of zebrafish immune cell development. We uncovered rich cellular diversity in the juvenile and adult zebrafish thymus, elucidated B- and T-cell developmental trajectories, and transcriptionally characterized subsets of hematopoietic stem and progenitor cells and early thymic progenitors. Our analysis permitted the identification of two dendritic-like cell populations and provided evidence in support of the existence of a pre-B cell state. Our results provide critical insights into the landscape of zebrafish immunology and offer a foundation for cellular and genetic studies.
Helminth-induced reprogramming of the stem cell compartment inhibits type 2 immunity
Authors: Danielle Karo-Atar, Shaida Ouladan, Tanvi Javkar, Loick Joumier, Macy K. Matheson, Sydney Merritt, Susan Westfall, Annie Rochette, Maria E. Gentile, Ghislaine Fontes, Gregory J. Fonseca, Marc Parisien, Luda Diatchenko, Jakob von Moltke, Mohan Malleshaiah, Alex Gregorieff, Irah L. King
Journal: The Journal of Experimental Medicine (2022)

Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine–driven differentiation of secretory epithelial lineages that promote their expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness, indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.
IgM antibodies derived from memory B cells are potent cross-variant neutralizers of SARS-CoV-2
Authors: Malika Hale, Jason Netland, Yu Chen, Christopher D. Thouvenel, Katherine Nabel Smith, Lucille M. Rich, Elizabeth R. Vanderwall, Marcos C. Miranda, Julie Eggenberger, Linhui Hao, Michael J. Watson, Charles C. Mundorff, Lauren B. Rodda, Neil P. King, Miklos Guttman, Michael Gale, Jonathan Abraham, Jason S. Debley, Marion Pepper, David J. Rawlings
Journal: The Journal of Experimental Medicine (2022)

Humoral immunity to SARS-CoV-2 can be supplemented with polyclonal sera from convalescent donors or an engineered monoclonal antibody (mAb) product. While pentameric IgM antibodies are responsible for much of convalescent sera’s neutralizing capacity, all available mAbs are based on the monomeric IgG antibody subtype. We now show that IgM mAbs derived from immune memory B cell receptors are potent neutralizers of SARS-CoV-2. IgM mAbs outperformed clonally identical IgG antibodies across a range of affinities and SARS-CoV-2 receptor-binding domain epitopes. Strikingly, efficacy against SARS-CoV-2 viral variants was retained for IgM but not for clonally identical IgG. To investigate the biological role for IgM memory in SARS-CoV-2, we also generated IgM mAbs from antigen-experienced IgM+ memory B cells in convalescent donors, identifying a potent neutralizing antibody. Our results highlight the therapeutic potential of IgM mAbs and inform our understanding of the role for IgM memory against a rapidly mutating pathogen.
A phase two study of high dose blinatumomab in Richter’s syndrome
Authors: Philip A. Thompson, Xianli Jiang, Pinaki Banerjee, Rafet Basar, Naveen Garg, Ken Chen, Mecit Kaplan, Vandana Nandivada, Ana Karen Nunez Cortes, Alessandra Ferrajoli, Michael J. Keating, Christine B. Peterson, Michael Andreeff, Katayoun Rezvani, William G. Wierda
Journal: Leukemia (2022)
Association of Gonadotropin-Releasing Hormone Agonists for Prostate Cancer With Cardiovascular Disease Risk and Hypertension in Men With Diabetes
Authors: E. Lin, Hans Garmo, Mieke Van Hemelrijck, Björn Zethelius, Pär Stattin, Emil Hagström, Jan Adolfsson, Danielle Crawley
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Men with type 2 diabetes have an increased risk of cardiovascular disease (CVD). Meanwhile, gonadotropin-releasing hormone (GnRH) agonists used in prostate cancer (PCa) are associated with increased risk of CVD. <h3>Objective</h3> To evaluate the association between GnRH agonist use, PCa diagnosis per se, and CVD risk in men with type 2 diabetes. <h3>Design, Setting, and Participants</h3> This nationwide population-based cohort study identified men with type 2 diabetes by use of data in the Prostate Cancer Data Base Sweden version 4.1 and the Swedish National Diabetes Register, with longitudinal data from 2006 to 2016. These data were used to create 2 cohorts, 1 including men with and without PCa and the other including men with PCa who received and did not receive GnRH agonists. Data analysis was conducted from January 2006 to December 2016. <h3>Exposures</h3> Treatment with GnRH agonists and PCa diagnosis were the primary exposures. <h3>Main Outcomes and Measures</h3> Primary outcome was a 10% increase in predicted 5-year CVD risk score. Secondary outcome was worsening hypertension as defined by the European Society of Hypertension Guidelines. Cox proportional hazards regression models were used to analyze the association. <h3>Results</h3> The PCa exposure cohort included 5714 men (median [IQR] age, 72.0 [11.0]), and the non-PCa cohort included 28 445 men without PCa (median [IQR] age, 72.0 [11.0]). The GnRH agonist–exposure cohort included 692 men with PCa who received a GnRH agonist, compared with 3460 men with PCa who did not receive a GnRH agonist. Men with PCa receiving GnRH agonists had an increased estimated 5-year CVD risk score compared with men without PCa (hazard ratio [HR], 1.25; 95% CI, 1.16-1.36) and compared with men with PCa not receiving GnRH agonists (HR, 1.53; 95% CI, 1.35-1.74). Men receiving GnRH agonists had decreased blood pressure compared with men without PCa (HR, 0.70; 95% CI, 0.61-0.80) and compared with men with PCa not receiving GnRH agonists (HR, 0.68; 95% CI, 0.56-0.82). <h3>Conclusions and Relevance</h3> In this population-based cohort study, there was an increased risk of CVD in men with type 2 diabetes who received a GnRH agonist for PCa. These findings highlight the need to closely control CVD risk factors in men with type 2 diabetes treated with GnRH agonists. The association between GnRH agonist use and decreased blood pressure levels warrants further study.
Effectiveness of Early Time-Restricted Eating for Weight Loss, Fat Loss, and Cardiometabolic Health in Adults With Obesity
Authors: Humaira Jamshed, Felicia L. Steger, David R. Bryan, Joshua S. Richman, Amy H. Warriner, Cody J. Hanick, Corby K. Martin, Sarah-Jeanne Salvy, Courtney M. Peterson
Journal: JAMA Internal Medicine (2022)

<h3>Importance</h3> It is unclear how effective intermittent fasting is for losing weight and body fat, and the effects may depend on the timing of the eating window. This randomized trial compared time-restricted eating (TRE) with eating over a period of 12 or more hours while matching weight-loss counseling across groups. <h3>Objective</h3> To determine whether practicing TRE by eating early in the day (eTRE) is more effective for weight loss, fat loss, and cardiometabolic health than eating over a period of 12 or more hours. <h3>Design, Setting, and Participants</h3> The study was a 14-week, parallel-arm, randomized clinical trial conducted between August 2018 and April 2020. Participants were adults aged 25 to 75 years with obesity and who received weight-loss treatment through the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital. <h3>Interventions</h3> All participants received weight-loss treatment (energy restriction [ER]) and were randomized to eTRE plus ER (8-hour eating window from 7:00 to 15:00) or control eating (CON) plus ER (≥12-hour window). <h3>Main Outcomes and Measures</h3> The co–primary outcomes were weight loss and fat loss. Secondary outcomes included blood pressure, heart rate, glucose levels, insulin levels, and plasma lipid levels. <h3>Results</h3> Ninety participants were enrolled (mean [SD] body mass index, 39.6 [6.7]; age, 43 [11] years; 72 [80%] female). The eTRE+ER group adhered 6.0 (0.8) days per week. The eTRE+ER intervention was more effective for losing weight (−2.3 kg; 95% CI, −3.7 to −0.9 kg;<i>P</i> = .002) but did not affect body fat (−1.4 kg; 95% CI, −2.9 to 0.2 kg;<i>P</i> = .09) or the ratio of fat loss to weight loss (−4.2%; 95% CI, −14.9 to 6.5%;<i>P</i> = .43). The effects of eTRE+ER were equivalent to reducing calorie intake by an additional 214 kcal/d. The eTRE+ER intervention also improved diastolic blood pressure (−4 mm Hg; 95% CI, −8 to 0 mm Hg;<i>P</i> = .04) and mood disturbances, including fatigue-inertia, vigor-activity, and depression-dejection. All other cardiometabolic risk factors, food intake, physical activity, and sleep outcomes were similar between groups. In a secondary analysis of 59 completers, eTRE+ER was also more effective for losing body fat and trunk fat than CON+ER. <h3>Conclusions and Relevance</h3> In this randomized clinical trial, eTRE was more effective for losing weight and improving diastolic blood pressure and mood than eating over a window of 12 or more hours at 14 weeks. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03459703
Breaking Down the Boxes—Time to Reshape Demographic Data
Authors: Tina Aswani-Omprakash, Abby L. Kaplan, Stacy A. Kahn
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Breaking Down the Boxes—Time to Reshape Demographic Data—Reply
Authors: Barbara H. Chaiyachati, Michelle-Marie Peña, Diana Montoya-Williams
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Treatment of <i>Clostridioides difficile</i> Infection
Authors: Kanika Sehgal, Adam S. Cifu, Sahil Khanna
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Preschool Readiness of Preterm-Born Children—The Hidden Impact of Familial Resilience
Authors: Mary Lauren Neel, Elsa K. Malmud, Nathalie L. Maitre
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal